Appropriate classification of fusion-driven bone and soft tissue neoplasms continues to evolve, often relying on the careful integration of morphologic findings with immunohistochemical, molecular, and clinical data. Herein, we present 3 cases of a morphologically distinct myxoid mesenchymal neoplasm with myogenic differentiation and novel CRTC1::MRTFB (formerly MKL2) gene fusion. Three tumors occurred in 1 male and 2 female patients with a median age of 72 years (range: 28-78). Tumors involved the left iliac bone, the right thigh, and the left perianal region with a median size of 4.0 cm (4.0-7.6 cm). Although 1 tumor presented as an incidental finding, the other 2 tumors were noted, given their persistent growth. At the time of the last follow-up, 1 patient was alive with unresected disease at 6 months, 1 patient was alive without evidence of disease at 12 months after surgery, and 1 patient died of disease 24 months after diagnosis. On histologic sections, the tumors showed multinodular growth and were composed of variably cellular spindle to round-shaped cells with distinct brightly eosinophilic cytoplasm embedded within a myxoid stroma. One tumor showed overt smooth muscle differentiation. Cytologic atypia and mitotic activity ranged from minimal (2 cases) to high (1 case). By immunohistochemistry, the neoplastic cells expressed focal smooth muscle actin, h-caldesmon, and desmin in all tested cases. Skeletal muscle markers were negative. Next-generation sequencing detected nearly identical CRTC1::MRTFB gene fusions in all cases. We suggest that myxoid mesenchymal tumors with myogenic differentiation harboring a CRTC1::MRTFB fusion may represent a previously unrecognized, distinctive entity that involves soft tissue and bone. Continued identification of these novel myxoid neoplasms with myogenic differentiation will be important in determining appropriate classification, understanding biologic potential, and creating treatment paradigms.
- MeSH
- Cell Differentiation * MeSH
- Adult MeSH
- Gene Fusion MeSH
- Oncogene Proteins, Fusion genetics MeSH
- Humans MeSH
- Biomarkers, Tumor genetics analysis MeSH
- Bone Neoplasms * genetics pathology MeSH
- Soft Tissue Neoplasms * genetics pathology MeSH
- Aged MeSH
- Trans-Activators genetics MeSH
- Transcription Factors * genetics MeSH
- Muscle Development genetics MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
Rhabdomyosarcoma (RMS) is a malignant tumour of soft tissues, occurring mainly in children and young adults. RMS cells derive from muscle cells, which due to mutations and epigenetic modifications have lost their ability to differentiate. Epigenetic modifications regulate expression of genes responsible for cell proliferation, maturation, differentiation and apoptosis. HDAC inhibitors suppress histone acetylation; therefore, they are a promising tool used in cancer therapy. Trichostatin A (TsA) is a pan-inhibitor of HDAC. In our study, we investigated the effect of TsA on RMS cell biology. Our findings strongly suggest that TsA inhibits RMS cell proliferation, induces cell apoptosis, and reactivates tumour cell differentiation. TsA up-regulates miR-27b expression, which is involved in the process of myogenesis. Moreover, TsA increases susceptibility of RMS cells to routinely used chemotherapeutics. In conclusion, TsA exhibits anti-cancer properties, triggers differentiation, and thereby can complement an existing spectrum of chemotherapeutics used in RMS therapy.
- MeSH
- Acetylation drug effects MeSH
- Apoptosis drug effects MeSH
- Cell Differentiation drug effects MeSH
- Epigenesis, Genetic drug effects genetics MeSH
- Histone Deacetylase Inhibitors pharmacology MeSH
- Hydroxamic Acids pharmacology MeSH
- Humans MeSH
- MicroRNAs metabolism MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Rhabdomyosarcoma metabolism MeSH
- Muscle Development drug effects genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
The bulbocavernosus (BC) is a sexually dimorphic muscle observed only in males. Androgen receptor knockout mouse studies show the loss of BC formation. This suggests that androgen signaling plays a vital role in its development. Androgen has been known to induce muscle hypertrophy through satellite cell activation and myonuclei accretion during muscle regeneration and growth. Whether the same mechanism is present during embryonic development is not yet elucidated. To identify the mechanism of sexual dimorphism during BC development, the timing of morphological differences was first established. It was revealed that the BC was morphologically different between male and female mice at embryonic day (E) 16.5. Differences in the myogenic process were detected at E15.5. The male BC possesses a higher number of proliferating undifferentiated myoblasts. To identify the role of androgen signaling in this process, muscle-specific androgen receptor (AR) mutation was introduced, which resulted in no observable phenotypes. Hence, the expression of AR in the BC was examined and found that the AR did not colocalize with any muscle markers such as Myogenic differentiation 1, Myogenin, and paired box transcription factor 7. It was revealed that the mesenchyme surrounding the BC expressed AR and the BC started to express AR at E15.5. AR mutation on the nonmyocytic cells using spalt-like transcription factor 1 (Sall1) Cre driver mouse was performed, which resulted in defective BC formation. It was revealed that the number of proliferating undifferentiated myoblasts was reduced in the Sall1 Cre:AR(L-/Y) mutant embryos, and the adult mutants were devoid of BC. The transition of myoblasts from proliferation to differentiation is mediated by cyclin-dependent kinase inhibitors. An increased expression of p21 was observed in the BC myoblast of the Sall1 Cre:AR(L-/Y) mutant and wild-type female. Altogether this study suggests that the nonmyocytic AR may paracrinely regulate the proliferation of myoblast possibly through inhibiting p21 expression in myoblasts of the BC.
- MeSH
- Receptors, Androgen genetics metabolism MeSH
- Time Factors MeSH
- Embryo, Mammalian embryology metabolism MeSH
- Immunohistochemistry MeSH
- Cyclin-Dependent Kinase Inhibitor p21 metabolism MeSH
- Microscopy, Electron, Scanning MeSH
- Mutation MeSH
- Myoblasts cytology metabolism MeSH
- Mice, Inbred ICR MeSH
- Mice, Knockout MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Perineum embryology MeSH
- Cell Proliferation MeSH
- Sex Factors MeSH
- Muscles embryology metabolism ultrastructure MeSH
- Pregnancy MeSH
- Transcription Factors genetics metabolism MeSH
- Muscle Development genetics physiology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
MicroRNAs (miRs) are small non-coding RNAs known to fulfill various functions in tissue development, function, and pathogenesis of various diseases, including cancer. Rhabdomyosarcoma (RMS) represents the most common soft tissue tumor in the pediatric population. miRs have been shown to play important roles in RMS pathogenesis and some of the studies suggest their potential as diagnostic, prognostic, and even therapeutic tools facilitating better management of this disease. This review summarizes current information about the role of miRs in the development of normal skeletal muscle and their deregulation in RMS.
- MeSH
- Muscle, Skeletal embryology growth & development physiology MeSH
- Humans MeSH
- MicroRNAs genetics MeSH
- Soft Tissue Neoplasms genetics MeSH
- Rhabdomyosarcoma genetics MeSH
- Muscle Development genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Many stress conditions are accompanied by skeletal muscle dysfunction and regeneration, which is essentially a recapitulation of the embryonic development. However, regeneration usually occurs under conditions of hypothalamus-pituitary-adrenal gland axis activation and therefore increased glucocorticoid (GC) levels. Glucocorticoid receptor (GR), the main determinant of cellular responsiveness to GCs, exists in two isoforms (GRalpha and GRbeta) in humans. While the role of GRalpha is well characterized, GRbeta remains an elusive player in GC signalling. To elucidate basic characteristics of GC signalling in the regenerating human skeletal muscle we assessed GRalpha and GRbeta expression pattern in cultured human myoblasts and myotubes and their response to 24-hour dexamethasone (DEX) treatment. There was no difference in GRalpha mRNA and protein expression or DEX-mediated GRalpha down-regulation in myoblasts and myotubes. GRbeta mRNA level was very low in myoblasts and remained unaffected by differentiation and/or DEX. GRbeta protein could not be detected. These results indicate that response to GCs is established very early during human skeletal muscle regeneration and that it remains practically unchanged before innervation is established. Very low GRbeta mRNA expression and inability to detect GRbeta protein suggests that GRbeta is not a major player in the early stages of human skeletal muscle regeneration.
- MeSH
- Cell Culture Techniques methods MeSH
- Dexamethasone therapeutic use MeSH
- Gene Expression genetics MeSH
- Financing, Organized MeSH
- Glucocorticoids genetics metabolism MeSH
- Real-Time Polymerase Chain Reaction utilization MeSH
- Humans MeSH
- Musculoskeletal System physiopathology MeSH
- Myoblasts, Skeletal physiology pathology drug effects MeSH
- Stress, Psychological metabolism physiopathology pathology MeSH
- Receptors, Glucocorticoid genetics metabolism MeSH
- Statistics as Topic MeSH
- Muscle Development physiology genetics drug effects MeSH
- Blotting, Western utilization MeSH
- Check Tag
- Humans MeSH
Caenorhabditis elegans has an unexpectedly large number (284) of genes encoding nuclear hormone receptors, most of which are nematode-specific and are of unknown function. We have exploited comparative two-dimensional chromatography of synchronized cultures of wild type C. elegans larvae and a mutant in nhr-40 to determine if proteomic approaches will provide additional insight into gene function. Chromatofocusing, followed by reversed-phase chromatography and mass spectrometry, identified altered chromatographic patterns for a set of proteins, many of which function in muscle and metabolism. Prompted by the proteomic analysis, we find that the penetrance of the developmental phenotypes in the mutant is enhanced at low temperatures and by food restriction. The combination of our phenotypic and proteomic analysis strongly suggests that NHR-40 provides a link between metabolism and muscle development. Our results highlight the utility of comparative two-dimensional chromatography to provide a relatively rapid method to gain insight into gene function.
- MeSH
- Caenorhabditis elegans chemistry metabolism MeSH
- Chromatography, Liquid methods MeSH
- Financing, Organized MeSH
- Caenorhabditis elegans Proteins analysis metabolism MeSH
- Proteome analysis metabolism MeSH
- Proteomics methods MeSH
- Receptors, Cytoplasmic and Nuclear physiology genetics MeSH
- Muscle Development genetics MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
